Underlying mechanism of the contractile dysfunction in atrophied ventricular myocytes from a murine model of hypothyroidism.

Hypothyroidism (Hypo) is a risk factor for cardiovascular diseases, including heart failure. Hypo rapidly induces Ca2+ mishandling and contractile dysfunction (CD), as well as atrophy and ventricular myocytes (VM) remodeling. Hypo decreases SERCA-to-phospholamban ratio (SERCA/PLB), and thereby contributes to CD. Nevertheless, detailed spatial and temporal Ca2+ cycling characterization in VM is missing, and contribution of other structural and functional changes to the mechanism underlying Ca2+ mishandling and CD, as transverse tubules (T-T) remodeling, mitochondrial density (Dmit) and energy availability, is unclear. Therefore, in a rat model of Hypo, we aimed to characterize systolic and diastolic Ca2+ signaling, T-T remodeling, Dmit, citrate synthase (CS) activity and high-energy phosphate metabolites (ATP and phosphocreatine). We confirmed a decrease in SERCA/PLB (59%), which slowed SERCA activity (48%), reduced SR Ca2+ (19%) and blunted Ca2+ transient amplitude (41%). Moreover, assessing the rate of SR Ca2+ release (dRel/dt), we found that early and maximum dRel/dt decreased, and this correlated with staggered Ca2+ transients. However, dRel/dt persisted during Ca2+ transient relaxation due to abundant late Ca2+ sparks. Isoproterenol significantly up-regulated systolic Ca2+ cycling. T-T were unchanged, hence, cannot explain staggered Ca2+ transients and altered dRel/dt. Therefore, we suggest that these might be caused by RyR2 clusters desynchronization, due to diminished Ca2+-dependent sensitivity of RyR2, which also caused a decrease in diastolic SR Ca2+ leak. Furthermore, Dmit was unchanged and CS activity slightly decreased (14%), however, the ratio phosphocreatine/ATP did not change, therefore, energy deficiency cannot account for Ca2+ and contractility dysregulation. We conclude that decreased SR Ca2+, due to slower SERCA, disrupts systolic RyR2 synchronization, and this underlies CD.

The 8-oxo-deoxyguanosine glycosylase increases its migration to mitochondria in compensated cardiac hypertrophy.

Cardiac hypertrophy is a compensatory mechanism maladapted because it presents an increase in the oxidative stress which could be associated with the development of the heart failure. A mechanism proposed is by mitochondrial DNA (mtDNA) oxidation, which evolved to a vicious cycle because of the synthesis of proteins encoded in the genome is committed. Therefore, the aim of the present work was to evaluate the mtDNA damage and enzyme repairing the 8-oxo-deoxyguanosine glycosylase mitochondrial isoform 1-2a (OGG1-2a) in the early stage of compensated cardiac hypertrophy induced by abdominal aortic constriction (AAC). Results showed that after 6 weeks of AAC, hearts presented a compensated hypertrophy (22%), with an increase in the cell volume (35%), mitochondrial mass (12%), and mitochondrial membrane potential (94%). However, the increase of oxidative stress did not affect mtDNA most probably because OGG1-2a was found to increase 3.2 times in the mitochondrial fraction. Besides, mitochondrial function was not altered by the cardiac hypertrophy condition but in vitro mitochondria from AAC heart showed an increased sensibility to stress induced by the high Ca2+ concentration. The increase in the oxidative stress in compensated cardiac hypertrophy induced the OGG1-2a migration to mitochondria to repair mtDNA oxidation, as a mechanism that allows maintaining the cardiac function in the compensatory stage.